San Raffaele Telethon Institute for Gene Therapy
The San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) was created in 1995 as a joint venture between the Telethon Foundation and IRCCS Ospedale San Raffaele, with the mission to perform cutting-edge research in gene and cell therapy and to translate its results into therapeutic advances, focusing on genetic diseases.
Overall, SR-Tiget represents a multi-disciplinary research environment, which provides a unique blend of scientific expertise in the development of innovative gene and cell therapy strategies, access to relevant preclinical models to evaluate their efficacy and safety, as well as competence in conducting early phase clinical trials. This provides a fertile ground for alliances with industrial partners, which possess the skills and resources required to address the regulatory hurdles and manufacturing needs to bring new therapies to registration and make them available to patients.
Research at SR-Tiget spans from basic research to pre-clinical studies to early phase clinical trials according to the following major aims:
- identifying the genetic bases and the pathophysiological processes underlying several types of inherited diseases, including primary immunodeficiencies and autoimmune/autoinflammatory diseases, hematologic diseases, inherited leukodystrophies and other lysosomal storage and neurodegenerative diseases;
- developing novel ex vivo or in vivo gene and cell therapy strategies for such diseases and validating them in ad hoc designed experimental models;
- ameliorating the performance and safety of gene transfer employed for these therapies, i.e. by stringently targeting transduction or expression of lentiviral vectors to the desired cell types and reducing their impact on endogenous transcription at genomic insertion sites;
- characterizing the biological properties of hematopoietic and neural stem and progenitor cells and of mesenchymal stromal cells targeted by these therapies and improving the procedures for their ex vivo isolation, genetic modification and transplantation;
- developing novel technological platforms, including targeted genome and epigenome editing using artificial enzymes with DNA sequence-specific activity (such as ZFN, TALEN and CRISPR-Cas9 nucleases) and scaffolds for ex vivo organoid culture (e.g. for hematopoietic stem cell niche reconstitution);
- investigating the cell types that mediate innate and adaptive immunity, with the aim to develop strategies to induce immunological tolerance to gene and cell products, in order to improve the efficacy and stability of such therapies;
- exploiting the platforms and strategies developed through the abovementioned investigations to design new gene and cell therapies for some common diseases, i.e. to induce tolerance in diabetes and other autoimmune diseases or, conversely, enhance adaptive immunity to cancer associated antigens.
SR-Tiget portfolio of gene and cell therapies now embraces the full spectrum of drug development up to the market. Notably, in May 2016 the European Commission granted marketing authorization for Strimvelis for the treatment of ADA-SCID, a severe form of immunodeficiency. Strimvelis, which is the first approved ex vivo gene therapy worldwide, has been developed at SR-Tiget and brought to the market under a strategic alliance with GSK. The successful results obtained with ADA-SCID provided a rationale for extending the HSC gene therapy approach to other diseases. In particular, two clinical trials for Wiskott-Aldrich Syndrome (WAS) and Metachromatic Leukodystrophy (MLD) started in 2010 and have shown persistent therapeutic benefit in the absence of treatment-related adverse events. A third trial, for beta‐thalassemia, started in 2015 and is showing promising preliminary results. In addition, a trial for Mucopolysaccharidosis type I (MPS-I) is planned to start in 2018.
The CLINICAL RESEARCH Units of SR-Tiget work in close collaboration with the Stem Cell Program and the Pediatric Immuno-Hematology Unit of IRCCS Ospedale San Raffaele.
To foster the development from bench to bedside of the new therapeutic strategies being investigated at SR-Tiget, the following structures have been established in the Institute:
First academic GLP Test Facility for performing biodistribution, toxicology/tumorigenicity and validation studies on gene and cell therapy products. Certified by the Italian Ministry of Health in March 2014; renewed in April 2016 and 2018.
Performs genome-wide profiling of vector integration sites as readout of cell growth at clonal level, in basic research studies and technology development, in preclinical safety studies and in gene therapy treated patients.
3. SR-Tiget clinical Lab
Performs analytical tests of samples from patients enrolled in clinical protocols, including Phase I clinical trials according to the minimum requirements of Determine AIFA 809/2015 and Good Clinical Laboratory Practice (GCLP) standards and in compliance with Good Clinical Practices (GCP).
4. Process Development Laboratory (in preparation)
To develop new protocols for vector production, gene editing and ex vivo cell manipulation in a context of GSP (Good Scientific Practices) and Quality by Design.
5. Bioinformatics core
Clinical research Unit
Epigenetic regulation and targeted genome editing
Gene and neural stem cell therapy for lysosomal storage diseases
Genomics of the innate immune system
Gene transfer into stem cell
Gene transfer technologies and new gene therapy strategies
Human hematopoietic development and disease modeling
Mechanisms of peripheral tolerance
Pathogenesis and therapy of primary immunodeficiencies
Pathogenesis and treatment of immune and bone diseases
Retrovirus-host interactions and innate immunity to gene transfer
Safety of gene therapy and insertional mutagenesis
Senescence in stem cell aging, differentiation and cancer
Raffaella Di Micco
Translational stem cell and leukemia
Targeted Cancer Gene Therapy
Raffaella Di Micco
Group leader, Senescence in stem cell aging, differentiation and cancer Unit
Group leader, Pathogenesis and therapy of primary immunodeficiencies Unit
Group leader, Human hematopoietic development and disease modeling Unit
Group leader, Gene transfer into stem cell Unit
Group leader, Translational stem cell and leukemia Unit
Group leader, Mechanisms of peripheral tolerance Unit
Group leader, Gene and neural stem cell therapy for lysosomal storage diseases Unit
Group leader, Retrovirus-host interactions and innate immunity to gene transfer Unit
Group leader, Epigenetic regulation and targeted genome editing Unit
Group leader, Safety of gene therapy and insertional mutagenesis Unit
Group leader, Gene transfer technologies and new gene therapy strategies Unit
Group leader, Genomics of the innate immune system Unit
Group leader, Pathogenesis and treatment of immune and bone diseases Unit
2 bioinformatician positions are immediately available in Safety and insertional mutagenesis Unit, headed by Eugenio Montini, at SR-Tiget
A Postdoctoral position is available at SR-Tiget in the Epigenetic regulation and targeted genome editing Unit, headed by Angelo Lombardo
One postdoctoral position is available at SR-Tiget in the field of human hematopoietic development and disease modeling
Two postdoctoral position are available in the the Retrovirus-Host Interactions and Innate Immunity to Gene Transfer lab, headed by Anna Kajaste-Rudnitski at SR-Tiget
Raffaella Di Micco awarded with the Robertson Stem Cell Prize
The prestigious recognition arrives for the first time in Italy and will support Di Micco’s research on blood stem cell therapies for rare genetic diseases
Else Kröner Fresenius Prize for biomedical research to Alessandro Aiuti
The Deputy Director of the San Raffaele-Telethon Institute for Gene Therapy in Milan awarded for his contribution to the development of innovative therapies for serious genetic diseases.
Gene therapy unveils family tree of blood stem cells
Study shows the role of different stem cells families both in the earliest and in the steady state phase after BM transplantation
Efficacy of gene therapy in treating Wiskott-Aldrich Syndrome
The clinical study demonstrates the effectiveness of gene therapy in treating Wiskott-Aldrich Syndrome
The 2019 Louis-Jeantet Prize awarded to Luigi Naldini
The director of the San Raffaele Telethon Institute for Gene Therapy wins the prize for his pioneering work on gene therapy
“Don’t-Eat-Me". Viral vectors resistant to capture by immune cells
Researchers obtained gene therapy vectors that escape capture by virus-clearing immune cells in the liver and spleen
A prestigious ERC grant to improve gene therapy
The ERC awarded 291 researchers from 40 different countries: among the winners Anna Kajaste-Rudnitski, group leader at SR-Tiget
A new ingredient to potentiate gene therapy
A study shows that a naturally occurring compound significantly increases the efficiency of lentiviral vector-mediated gene transfer in blood stem cells